Antisense Oligonucleotide Tofersen Gains Steam With Positive Phase 1/2 Results


The vice president and head of the Neuromuscular Development Unit at Biogen, and study coauthor, discussed the implications of recently published data on tofersen and the ongoing work in phase 3.

Dr Toby Ferguson

Toby Ferguson, MD, PhD, vice president, and head, Neuromuscular Development Unit, Biogen

Toby Ferguson, MD, PhD

This is the second of a 2-part interview. To read part 1, click here.

The SOD1 gene mutation is believed to be a genetic driver of ALS in approximately 2% of all cases, and with positive signs from recently published data on tofersen, a gene therapy targeting SOD1 developed by Biogen, the potential of that population gaining a treatment is growing.

Tofersen was assessed in a range of doses—20 mg (n = 10), 40 mg (n = 9), 60 mg (n = 9), and 100 mg (n = 10)—and compared to placebo across those groups (n = 12). All told, at Day 85, differences between the tofersen groups and placebo were 2 percentage points (95% CI, −18 to 27) for the 20-mg dose, −25 percentage points (95% CI, −40 to −5) for the 40-mg dose, −19 percentage points (95% CI, −35 to 2) for the 60-mg dose, and −33 percentage points (95% CI, −47 to −16) for the 100-mg dose.1,2

Respectively, the geometric mean ratios of the SOD1 protein concentrations among participants who received tofersen decreased overall by 1%, 27%, 21%, and 36%. Among those who received placebo, the ratio decreased by 3%. A phase 3 study, VALOR (NCT02623699), is currently ongoing and will assess the efficacy and safety of tofersen versus placebo in adults with SOD1-ALS.

To find out more about the implications of these data and the ongoing work, NeurologyLive spoke with study coauthor Toby Ferguson, MD, PhD, vice president, and head, Neuromuscular Development Unit, Biogen.

NeurologyLive: What's the significance of these data for that patient population and the providers that are treating and managing these patients?

Toby Ferguson, MD, PhD: For providers who are caring for SOD1 ALS patients, it certainly bears consideration for if this would be an appropriate therapy for them, should it be approved. It's not there yet, of course, but at least it is something they can highlight for their patients that exists, in the sense that this may be coming. Should we do genetic testing for SOD1? I think there's maybe a general consideration of if we should look more carefully for SOD1 patients. We know that with SOD1 patients, it's often inherited family to family, but there are certainly a number of cases that have been documented where SOD1 patients are found by screening the general ALS population. From the provider point of view, it really highlights a hope for SOD1 patients that something may come in the near term with the readout of the phase 3 study, VALOR. But, also the practical consideration of starting to think about genetic testing for SOD1 patients more widely. So genetic testing for SOD1 and other forms of ALS—the genetic forms are variable—is something to think about in clinic, for example.

With regard to the phase 3 trial, VALOR, what are the are the primary end points being explored?

The key points are that it's currently ongoing. We're creating a mixture of fast-progressing patients and slow-progressing patients, and the primary end point is ALSFS-R and survival, which is a conventional end point for phase 3 for ALS.

How does tofersen potentially stand out compared to the currently available agents for ALS?

There are 2 currently approved medications. There's riluzole, which has been around since the 1990s, and there is edavarone (Radicava; MT Pharma), which was recently approved. Those medications provide some benefit for patients, but there remains a sort of therapeutic gaps for these patients. I think the main distinction I would draw between those medications and tofersen really is that this is a genetically targeted therapy. That really, its goal is to treat the underlying mechanism of disease. That's the key distinction, that it really addresses that underlying cause of disease. That provides some of the excitement around this molecule, that this really is precision medicine for these SOD1 patients.

How have the lessons learned with tofersen been applied to Biogen's clinical developments in ALS?

We've taken some lessons learned from EMPOWER, our large phase 3 study that wasn't successful in 2013. There, I think, broadly that sort of suggested that we should refocus our efforts on genetically targeted therapies, and the leading effort there is tofersen. The experience in the phase 1/2 of tofersen has highlighted the potential importance and sort of validated the targeting of genetic populations. We've also obtained some general learnings about how to run ALS trials, the utility of biomarkers—for example, neurofilament may be broadly applicable across genetic and non-genetic forms ALS. I think that's a key learning moving forward.

Then, in terms of pipeline, we have currently BIIB078, which is an ASO for the C9orf72 repeat expansion that is the most common genetic cause of ALS. We're excited about that. We have an ongoing a small molecule BIIB100. That's in early phase development and that's for the broader ALS population. Then, in the near future we're going to announce another ASO collaboration with Ionis around developing an ASO for ataxin 2 reduction, which could be a possible therapy for the broader ALS population. Particularly, the C9 and ataxin 2 trials have taken direct lessons from the SOD trials particularly, in those efforts of recruiting patients, doing genetic testing, operationalizing the trial, etc.

Anything else you'd like to add?

I used to take care of ALS patients before I came to Biogen, and one of the reasons I came to Biogen was because I came just after EMPOWER, and I was excited to work on ALS after a big failure. What I mean by that is I was excited to be part of a company that was willing to reinvest and keep going. Neurologic disease drug development, and particularly ALS drug development is not easy. Working with Biogen to develop the molecule, to learn those lessons and move forward in ALS is really quite exciting. What I often think about is a patient I took care of right before I left academia. He was one of the last patients I saw clinically for ALS. A young man with a tough life, and he was out of work was a carpenter had come to see me for what he thought was a pinched nerve—just weakness in the right hand. I talked to him and his fiancé and it became pretty clear within about 20 to 30 minutes that he had ALS. I would love to be able to say in the future to patients that we have meaningful things to offer them for their disease and not have to tell most patients, like that young man, that you have fatal disease. That opportunity, this trial, and the data we've shown, represents a little bit of a step forward in offering hope to patients.

Transcript edited for clarity.


1. Miller T, Cudkowicz M, Shaw PJ, et al. Phase 1—2 Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS. N Engl J Med. 2020; 383:109-119. doi: 10.1056/NEJMoa2003715

2. The New England Journal of Medicine Publishes Final Results from Phase 1/2 Study of Tofersen for a Genetic Form of ALS [press release]. Cambridge, MA. Biogen. Published July 8, 2020. Accessed July 9, 2020.

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